Fragile X syndrome (FXS) is caused by the absence of FMRP, a negative regulator of mRNA translation. In this proposed Fragile X Center, Gary Bassell, Erick Klann, and Joel Richter demonstrate that depletion or inhibition of molecules that alter the translational landscape reverse excessive protein synthesis and FXS pathophysiological phenotypes in mice. These molecules include PI3 kinase, which when pharmacologically inactivated restores dysregulated protein synthesis and dendritic spine morphology that characterize FXS (Bassell Project), p70S6 kinase 1 (S6K1), which when genetically ablated corrects molecular, synaptic and behavioral phenotypes displayed by FXS mice (Klann Project); and the cytoplasmic polyadenylation element binding protein (CPEB), whose deficiency rescues inappropriate protein synthesis, synapse dysregulation, and behavioral abnormalities that are prominent features of FXS. These discoveries provide an unprecedented opportunity to alter the translational landscape and ameliorate symptoms of FXS. The Principal Investigators, together with an RNA Sequencing/Bioinformatics Core, will use innovative molecular biology to identify mRNAs whose translation is rescued when PI3K, S6K, and CPEB are ablated or inhibited, which will define the underlying molecular basis of FXS and indicate novel therapies to treat the disease. The investigators will work with an Electrophysiology/Animal Behavior Core to assess how rescued protein synthesis regulates synapse efficacy and higher cognitive function. The investigators work with both research cores to explore molecular mechanisms of rescued translation and apply the methods and knowledge gained from mouse models of FXS to assess molecular causation of FXS in human cells. The investigators will work with an Administrative Core to ensure scientific excellence in the Fragile X Center.